The sarcoglycan complex is a group of single pass transmembrane proteins (.alpha.-, .beta.-, .iota.- and .gamma.-sarcoglycan) which is tightly associated with sarcospan to form a subcomplex within the dystrophin-glycoprotein complex (DGC) in skeletal and cardiac muscle (Campbell et al., Nature 338: 259-362 (1989); Yoshida et al., J. Biochem. 108: 748-752 (1990); Crosbie et al., J. Cell Biol. 145: 153-165 (1999)). The DGC is further comprised of dystrophin, the dystroglycan complex and the syntrophins (Hoffman et al., Cell 51: 919-928 (1987); Froehner et al., Soc. Gen. Physiol. Ser. 52: 197-207 (1997); Durbeej et al., Curr. Opin. Cell. Biol. 10: 594-601 (1998)). The expression of the sarcoglycan-sarcospan complex is necessary to target dystroglycan to the sarcolemma (Duclos et al., J. Cell Biol. 142: 1461-1471 (1998); Duclos et al., Neuromusc. Disord. 8: 30-38 (1998); Holt et al., Mol. Cell 1: 841-848 (1998); Straub et al., Am. J. Path. 153: 1623-1630 (1998)) which in turn confers a link between the extracellular matrix and the F-actin cytoskeleton (Ervasti et al., J. Cell Biol. 122: 809-823 (1993)). Thus, the DGC is thought to protect muscle cells from contraction-induced damage (Petrof et al., Proc. Natl. Acad. Sci. USA 90: 3710-3714 (1993)). In agreement with this hypothesis, mutations in the genes for the sarcoglycans, dystrophin and laminin .alpha.2 chain are responsible for limb-girdle muscular dystrophy, Duchenne/Becker muscular dystrophy and congenital muscular dystrophy respectively (Straub et al., Curr. Opin. Neurol. 10: 168-175 (1997); Lim et al., Curr. Opin. Neurol. 11: 443-452 (1998)). Clinical evidence of cardiomyopathy is variably present in these muscular dystrophies (Towbin, J. A., Curr. Opin. Cell Biol. 10: 131-139 (1998)) but a correlation between the primary mutation of the sarcoglycan genes and cardiomyopathy is yet to be established (Melacini et al., Muscle & Nerve 22: 473-479 (1999)).
Dilated cardiomyopathy is a multifactorial disease that includes both inherited and acquired forms of cardiomyopathy. Inherited cardiomyopathy in humans can be associated with genetic defects occurring in components of the dystrophin-glycoprotein complex (DGC) (Towbin, J. A., Curr. Opin. Cell Biol. 10: 131-139 (1998)). Mutations in the dystrophin gene lead to a high incidence of cardiomyopathy in Duchenne and Becker muscular dystrophy patients (DMD/BMD) and can cause X-linked dilated cardiomyopathy (Towbin, J. A., Curr. Opin. Cell Biol. 10: 131-139 (1998)). In addition to these primary genetic causes of cardiomyopathy, recent data suggest that disruption of the DGC underlie the cardiomyopathy associated with enteroviral infection (Badorff et al., Nat. Med. 5: 320-326 (1999)). Consequently, evidence is accumulating that the DGC plays a critical role in the pathogenesis of some forms of inherited and acquired cardiomyopathy. Several components of the DGC are also expressed in smooth muscle (Houzelstein et al., J. Cell Biol. 119: 811-821 (1992); North et al., J. Cell Biol. 120: 1159-1167 (1993); Ozawa, et al., Hum. Mol. Gen. 4: 1711-1716 (1995); Durbeej et al., Curr. Opin. Cell. Biol. 10: 594-601 (1998)). Interestingly, potential smooth muscle dysfunction has been described in patients with Duchenne muscular dystrophy (Bahron et al., N. Engl. J. Med. 319: 15-18 (1998); Jaffe et al., Arch. Phys. Med. Rehabil. 71: 742-744 (1990)). However, no smooth muscle dysfunction has been reported in patients with limb-girdle muscular dystrophy.
Recently, a fifth sarcoglycan, .epsilon.-sarcoglycan, was cloned and shown to be highly homologous to .alpha.-sarcoglycan (Ettinger et al., J. Biol. Chem. 272: 32534-32538 (1997); McNally et al., FEBS Lett. 422: 27-32 (1998)). .epsilon.-sarcoglycan is expressed in skeletal and cardiac muscle, but also in several non-muscle tissues. Whether .epsilon.-sarcoglycan is associated with the other sarcoglycans in striated muscle is yet to be determined. At the immunofluorescence level, however, it has been shown that .epsilon.-sarcoglycan is still present in skeletal muscle of a-sarcoglycan deficient (Sgca-null mice) mice although the other sarcoglycans are greatly reduced (Duclos et al., J. Cell Biol. 142: 1461-1471 (1998)). This indicates that .epsilon.-sarcoglycan is not an additional member of the known tetrameric complex of .alpha.-, .beta.-, .gamma.- and .delta.-sarcoglycan in skeletal muscle but may be part of a distinct complex at the sarcolemma.
Sgca-null mice have recently been reported to display a progressive muscular dystrophy (Duclos et al., J. Cell Biol. 142: 1461-1471 (1998)). The primary absence of .alpha.-sarcoglycan was accompanied by the concomitant loss of .beta.-,.gamma.- and .delta.-sarcoglycan and sarcospan in skeletal and cardiac muscle fibers, a phenomenon that is also observed in human forms of sarcoglycanopathies (Lim et al., Curr. Opin. Neurol. 11: 443-52 (1998)). Interestingly, although the SG-SSPN complex was absent from the cardiac muscle membrane, no morphological signs of cardiomyopathy were observed (Duclos et al., J. Cell Biol. 142: 1461-1471 (1998)).